Project Summary. Alzheimer's disease (AD) is a chronic progressive neurodegenerative disorder that accounts for 60-70% of all cases of dementia. Genetic studies reported the possible causative role of amyloid- ? (A?), which is derived from the amyloid precursor protein (APP), in the development of AD. The accumulation of A? peptides in the brain can initiate the pathophysiology of AD, leading to neurofibrillary tangles and neurodegeneration. Preclinical and postmortem studies demonstrate a significant association between inflammatory pathways and the development of AD pathology. However, previous studies have focused mostly on innate immune cells. Alterations in the immune system, including T cells, occur with aging, likely contributing to the development of infections and malignancies. In human T cells, probably the most prominent change with aging is memory CD8+ T cell expansion in peripheral blood although alterations in CD4+ T cell subsets are reported as well. We found the age-associated expansion of human effector memory (EM, CCR7-CD45RA+/-) CD8+ T cells expressing low levels of IL-7 receptor alpha (IL-7R?low) which have distinct characteristics including effector molecules, transcription factors, and DNA methylation profiles. Recently, we investigated the possible relationship of this age-associated expansion of IL-7R?low EM CD8+ T cells with the global transcriptomic profile of peripheral blood cells in humans. Crossing differentially expressed genes (DEGs) in IL-7R?low EM CD8+ T cells against age-associated genes from human peripheral blood revealed an age-associated gene expression signature of the IL-7R?low EM CD8+ T cells that corresponded to 15% of the age-associated genes (244/1,497) reported by a meta-analysis study on human peripheral whole blood from approximately 15,000 individuals. A recent study reported the expansion of CD45RA+ EM CD8+ T cells in peripheral blood and cerebrospinal fluids of patients with dementia or mild cognitive impairment (MCI) due to AD, correlating with cognition. Importantly, such cells are mostly IL-7R?(CD127)low cells. Thus, we will investigate the possible implication of the age-associated expansion of IL-7R?low cells in AD based on the hypothesis that patients with AD have increased levels of IL-7R?low EM CD8+ T cell gene signature and an expansion of these cells in peripheral blood, correlating with measures of AD severity and brain synaptic density. The goal of the proposal is to test the hypothesis with the following aims: 1) Aim 1. Elucidate that patients with AD have increased levels of IL-7R?low EM CD8+ T cell gene signature in peripheral blood which correlate with disease severity and brain synaptic density; and 2) Aim 2. Elucidate that patients with AD have an altered T cell profile correlating with disease severity and brain synaptic density. Overall, our supplement proposal is unique and significant since it conducts in-depth studies on the role of CD8+ T cells, especially IL- 7R?low EM cells, in AD, which opens a new area of research in both healthy aging and AD.